Long term memory (LTM) involves induction of a cascade of gene expression (Davis, H. P. and Squire, L. R., Psychol. Bull., 96:518-559 (1984); Tully, T. et al., Cell, 79:35-47 (1994); Yin, J. C. et al., Cell, 79:49-58 (1994); Yin, J. C. et al., Cell, 81:107-115 (1995); Josselyn, S. A. et al., J. Neurosci., 21:2404-2412 (2001); Alberini, C. M. et al., Cell, 76:1099-1114 (1994); and Taubenfeld, S. M. et al., J. Neurosci., 21:84-91 (2001)) under control of the CREB transcription factor (Davis, H. P. and Squire, L. R., Psychol. Bull., 96:518-559 (1984); Tully, T. et al., Cell, 79:35-47 (1994); Yin, J. C. et al., Cell, 79:49-58 (1994); Yin, J. C. et al., Cell, 81:107-115 (1995); Josselyn, S. A. et al., J. Neurosci., 21:2404-2412 (2001); Alberini, C. M. et al., Cell, 76:1099-1114 (1994): and Taubenfeld, S. M. et al., J. Neurosci., 21:84-91 (2001)), which leads to structural and functional changes in specific synapses (Bartsch, D. et al. Cell, 83:979-992 (1995); and Dash, P. K. et al., Nature, 345:718-721 (1990)). LTM is disrupted by induced over-expression of a CREB transgene in flies (Yin, J. C. et al., Cell, 79:49-58 (1994)), by partial knock-out of CREB in mice (Bourtchuladze, R. et al., Cell, 79:59-68 (1994)), by knock-down of CREB with anti-sense RNA in rats (Guzowski, J. F. and McGaugh, J. L., Proc. Natl. Acad. Sci. USA, 94:2693-2698 (1997); and Lamprecht, R. et al., J. Neurosci., 17:8443-8450 (1997)) or by induced over expression of a dominant-negative CREB in mice (Kida, S. et al., Nat. Neurosci., 5:348-355 (2002); and Pittenger, C. et al., Neuron, 34:447-462 (2002)). Synaptic plasticity is disrupted similarly in Aplysia (Bartsch, D. et al., Cell, 83:979-992 (1995)), in flies (Davis, G. W. et al., Neuron, 17:669-679 (1996); and Sanyal, S. et al., Nature, 416:870-874 (2002)) and in mice (Bourtchuladze, R. et al., Cell, 79:59-68 (1994); Barco, A. et al., Cell, 108:689-703 (2002); and Casadio, A. et al., Cell, 99:221-237 (1999)). Strikingly, over expression of CREB activator in transgenic flies, or in virus-infected rats, enhances LTM (Yin, J. C. et al., Cell, 81:107-115 (1995); and Josselyn, S. A. et al., J. Neurosci., 21:2404-2412 (2001)), while analogous modulations of CREB activator enhance (i) long-term facilitation (LTF) and the concomitant growth of synaptic connections in sensorimotor neuron co-cultures of Aplysia (Bartsch, D. et al., Cell, 83:979-992 (1995)) and (ii) long-term potentiation (LTP) in rat hippocampus (Barco, A. et al., Cell, 108:689-703 (2002)). These convergent data establish that long-term memory (LTM) formation requires gene transcription (Yin, J. C. et al., Cell, 81:107-115 (1995); Abel, T. et al., Science, 279:338-341 (1998); and Tully, T., Proc. Natl. Acad. Sci. USA, 94:4239-4241 (1997)).
This insight has raised two new questions. First, specifically what genes are regulated during LTM formation? Attempts to answer this question have been pursued with in vitro models of neuronal plasticity, with strong pharmacological stimulation in vivo and, in a few cases, with behavioral training (Cole, A. J. et al., Nature, 340:474-476 (1989); Hevroni, D. et al., J. Mol. Neurosci., 10:75-98 (1998); Irwin, L. N., Brain Res. Mol. Brain Res., 96:163-169 (2001); Luo, Y. et al., J. Mol. Neurosci., 17:397-404 (2001); Cavallaro, S. et al., Eur. J. Neurosci., 13:1809-1815 (2001); Nedivi, E. et al., Nature, 363:718-722 (1993); and Nedivi, E. et al., Proc. Natl. Acad. Sci. USA, 93:2048-2053 (1996)). Second, how does a transcriptional response in the cell nucleus tag only a subset of synapses involved in LTM (Barco, A. et al., Cell, 108:689-703 (2002); Casadio, A. et al., Cell, 99:221-237 (1999); Frey, U. and Morris, R. G., Nature, 385:533-536 (1997); Martin, K. C. et al., Cell, 91:927-938 (1997); Steward, O. et at, Neuron, 21:741-751 (1998); Steward, O. and Schuman, E. M., Annu. Rev. Neurosci., 24:299-325 (2001); Steward, O. and Worley, P. F., Proc. Natl. Acad. Sci. USA, 98:7062-7068 (2001); Steward, O. and Worley, P. F., Neuron, 30:227-240 (2001); and Steward, O. and Worley, P., Results Probl. Cell. Differ., 34:1-26 (2001))? Thus far, analyses of in vitro models of synaptic plasticity have described the cellular phenomenology of synapse specific modification but have not yet identified the cellular machinery or established a connection to memory.